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. 2000 Jan 18;82(3):629–634. doi: 10.1054/bjoc.1999.0974

Mechanistic aspects of the cytotoxic activity of glufosfamide, a new tumour therapeutic agent

H Seker 1, B Bertram 1, A Bürkle 2, B Kaina 3, J Pohl 4, H Koepsell 5, M Wießler 1
PMCID: PMC2363326  PMID: 10682676

Abstract

β- D -Glucosyl-ifosfamide mustard (D 19575, glc-IPM, INN = glufosfamide) is a new agent for cancer chemotherapy. Its mode of action, which is only partly understood, was investigated at the DNA level. In the breast carcinoma cell line MCF7 glufosfamide inhibited both the synthesis of DNA and protein in a dose-dependent manner, as shown by the decreased incorporation of [3H-methyl]-thymidine into DNA and [14C]-methionine into protein of these cells. Treatment of MCF7 cells with 50 μM glufosfamide was sufficient to trigger poly(ADP-ribose) polymerase (PARP) activation, as revealed by immunofluorescence analysis. Both CHO-9 cells, which are O6-methylguanine-DNA methyltransferase (MGMT)-deficient, and an isogenic derivative, which has a high level of MGMT, showed the same cytotoxic response to β- D -glc-IPM, indicating that the O6position of guanine is not the critical target for cytotoxicity. By contrast, a sharp decrease in survival of cross-link repair deficient CL-V5 B cells was observed already at concentrations of 0.1 m Mβ- D -glc-IPM, whereas the wild-type V79 cells showed a 90% reduction in survival only after treatment with 0.5 m M of this compound. The therapeutically inactive β- L -enantiomer of glufosfamide also showed genotoxic effects in the same assays but at much higher doses. This was probably due to small amounts of ifosfamide mustard formed under the conditions of incubation. The results indicate that the DNA crosslinks are the most critical cytotoxic lesions induced by β- D -glc-IPM. © 2000 Cancer Research Campaign

Keywords: β- D -glucosyl-ifosfamide mustard, tumour therapy, poly(ADP-ribose) polymerase, DNA repair deficiency

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Selected References

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  1. Bürkle A., Chen G., Küpper J. H., Grube K., Zeller W. J. Increased poly(ADP-ribosyl)ation in intact cells by cisplatin treatment. Carcinogenesis. 1993 Apr;14(4):559–561. doi: 10.1093/carcin/14.4.559. [DOI] [PubMed] [Google Scholar]
  2. Hemminki K., Kallama S. Reactions of nitrogen mustards with DNA. IARC Sci Publ. 1986;(78):55–70. [PubMed] [Google Scholar]
  3. Kaina B., Fritz G., Mitra S., Coquerelle T. Transfection and expression of human O6-methylguanine-DNA methyltransferase (MGMT) cDNA in Chinese hamster cells: the role of MGMT in protection against the genotoxic effects of alkylating agents. Carcinogenesis. 1991 Oct;12(10):1857–1867. doi: 10.1093/carcin/12.10.1857. [DOI] [PubMed] [Google Scholar]
  4. Kawamitsu H., Hoshino H., Okada H., Miwa M., Momoi H., Sugimura T. Monoclonal antibodies to poly(adenosine diphosphate ribose) recognize different structures. Biochemistry. 1984 Jul 31;23(16):3771–3777. doi: 10.1021/bi00311a032. [DOI] [PubMed] [Google Scholar]
  5. Lindahl T., Satoh M. S., Poirier G. G., Klungland A. Post-translational modification of poly(ADP-ribose) polymerase induced by DNA strand breaks. Trends Biochem Sci. 1995 Oct;20(10):405–411. doi: 10.1016/s0968-0004(00)89089-1. [DOI] [PubMed] [Google Scholar]
  6. Monks A., Scudiero D. A., Johnson G. S., Paull K. D., Sausville E. A. The NCI anti-cancer drug screen: a smart screen to identify effectors of novel targets. Anticancer Drug Des. 1997 Oct;12(7):533–541. [PubMed] [Google Scholar]
  7. Pfuhler S., Wolf H. U. Detection of DNA-crosslinking agents with the alkaline comet assay. Environ Mol Mutagen. 1996;27(3):196–201. doi: 10.1002/(SICI)1098-2280(1996)27:3<196::AID-EM4>3.0.CO;2-D. [DOI] [PubMed] [Google Scholar]
  8. Pohl J., Bertram B., Hilgard P., Nowrousian M. R., Stüben J., Wiessler M. D-19575--a sugar-linked isophosphoramide mustard derivative exploiting transmembrane glucose transport. Cancer Chemother Pharmacol. 1995;35(5):364–370. doi: 10.1007/s002800050248. [DOI] [PubMed] [Google Scholar]
  9. Shaw I. C., Graham M. I. Mesna--a short review. Cancer Treat Rev. 1987 Jun;14(2):67–86. doi: 10.1016/0305-7372(87)90041-7. [DOI] [PubMed] [Google Scholar]
  10. Stüben J., Port R., Bertram B., Bollow U., Hull W. E., Schaper M., Pohl J., Wiessler M. Pharmacokinetics and whole-body distribution of the new chemotherapeutic agent beta-D-glucosylisophosphoramide mustard and its effects on the incorporation of [methyl-3H]-thymidine in various tissues of the rat. Cancer Chemother Pharmacol. 1996;38(4):355–365. doi: 10.1007/s002800050495. [DOI] [PubMed] [Google Scholar]
  11. Telleman P., Overkamp W. J., van Wessel N., Studzian K., Wetselaar L., Natarajan A. T., Zdzienicka M. Z. A new complementation group of mitomycin C-hypersensitive Chinese hamster cell mutants that closely resembles the phenotype of fanconi anemia cells. Cancer Res. 1995 Aug 1;55(15):3412–3416. [PubMed] [Google Scholar]
  12. Veyhl M., Wagner K., Volk C., Gorboulev V., Baumgarten K., Weber W. M., Schaper M., Bertram B., Wiessler M., Koepsell H. Transport of the new chemotherapeutic agent beta-D-glucosylisophosphoramide mustard (D-19575) into tumor cells is mediated by the Na+-D-glucose cotransporter SAAT1. Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):2914–2919. doi: 10.1073/pnas.95.6.2914. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Workman P. Towards intelligent anticancer drug screening in the post-genome era? Anticancer Drug Des. 1997 Oct;12(7):525–531. [PubMed] [Google Scholar]
  14. de Murcia G., Ménissier de Murcia J. Poly(ADP-ribose) polymerase: a molecular nick-sensor. Trends Biochem Sci. 1994 Apr;19(4):172–176. doi: 10.1016/0968-0004(94)90280-1. [DOI] [PubMed] [Google Scholar]

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